Immunosuppression, Liver Injury and Post-transplant HCV Recurrence

S. Ciesek; H. Wedemeyer

Disclosures

J Viral Hepat. 2012;19(1):1-8. 

In This Article

Prevention of HCV Re-infection After Liver Transplantation

Considering the severe clinical course of post-transplant hepatitis C, one of the major unmet needs is the development of strategies to prevent re-infection of the liver graft after transplantation. Pretransplant treatment with PEG-IFNa and ribavirin of patients on the waiting list to prevent HCV reinfection is possible only in few individuals as PEG-IFNa treatment can induce severe infectious complications in decompensated liver disease.[37,38] Moreover, no prophylactic vaccine is yet available to prevent HCV infection.[39] Thus, alternative strategies to prevent HCV reinfection during or very early after transplantation should be explored.

In general, agents preventing viral cell entry should be of particular value (Fig. 1). These include antibodies against one or all essential HCV cellular entry factors, neutralizing antibodies against the HCV envelope proteins E1 and/or E2 envelope or drugs targeting HCV entry by interaction with the virion or a cellular entry factor.

Figure 1.

Targets to prevent hepatitis C virus recurrence.

Four cellular factors have been described as essential for HCV entry: the tetraspanin molecule CD81, the scavenger receptor class B member I (SR-BI) and the tight junction proteins claudin-1 and occludin.[40] Interestingly, neutralizing antibodies against CD81 are able to block HCV entry in vitro and also in immunodeficient mice transplanted with human hepatocytes, the best currently available small animal model of HCV infection.[41] Anti-CD81 antibodies are currently in early clinical development but programs using antibodies against the other three entry factors are less advanced.

Neutralizing antibodies against the HCV envelope proteins E1 and E2 could also represent a promising approach to avoid HCV re-infection. However, efforts to elicit neutralizing antibody responses by immunization with E1E2 envelope proteins have had limited success. The main challenge here is the enormous genetic variability of the virus. Present within the chronically infected host is not a single isolate of HCV but rather a population of related yet different viral variants that has been referred to as a 'quasispecies swarm'. The swarm contains a vast repertoire of preformed variants that allow rapid escape from selective pressures such as neutralizing antibodies or anti-viral drugs. It has been shown that during chronic infection, HCV continuously escapes from the host's neutralizing antibody response.[35,42] Nonetheless, efforts to target HCV glycoproteins continue and recently, Garrone et al.[43] reported the development of a vaccine platform to generate HCV-neutralizing antibodies that are based on retrovirus-derived virus-like particles pseudotyped with heterologous E1 and/or E2 proteins. These particles induced neutralizing antibodies in mice and also in macaques and cross-neutralized other HCV genotypes. Overall, the application of broad cross-neutralizing anti-HCV antibodies to prevent HCV reinfection still seems to be reasonable approach. This strategy has been highly successful in hepatitis B virus infection where the combination of passive immunization with anti-HBs antibodies and HBV polymerase inhibitors is able to prevent HBV reinfections in all patients.[44]

Another possibility to inhibit HCV entry is the development of small molecules targeting one of the four cellular entry factors. ITX 5061 is an orally bioavailable compound blocking the HCV receptor scavenger receptor BI protein.[45] ITX-5061 had a good safety profile in animal toxicology studies and also in clinical studies. Currently, the potency of ITX-5061 is evaluated in an open-label, proof-of-concept Phase 1b study in liver-transplanted patients (http://www.clinicaltrials.gov).

Silibinin, a major component of silymarin, is a plant-derived compound that is used for the treatment of HCV infection although its precise mechanism of action is still not known in detail.[46] In 2010, it was shown for the first time that high doses of intravenous silibinin monotherapy prevented graft re-infection after OLT in a patient with chronic hepatitis C[47] which has been confirmed in another case report.[48] However, a much larger controlled study is needed to verify that intravenous silibinin is indeed safe and effective to prevent HCV re-infection after liver transplantation.

Recently, two other already well-known molecules have been shown to inhibit HCV entry: the green tea catechin EGCG and the tyrosine kinase inhibitor erlotinib. Erlotinib blocks HCV entry by inhibition of the activity of the EGF-receptor which is required for formation of CD81-claudin-1 co-receptor associations.[49] EGCG inhibits viral attachment to the target cell as well as cell-to-cell transmission between adjacent cells.[50] Both drugs are already FDA approved for other clinical applications; and EGCG is known to be innocuous in humans, readily available and cheap. Both inhibitors may provide a new approach to prevent HCV infection in the setting of liver transplantation, and future clinical studies are needed to test these in vitro observations in patients.

Besides entry blockers, more advanced direct acting antivirals (DAA) targeting other phases of the replication cycle may also be useful to prevent HCV re-infection. However, almost all DAAs in development have only been tested in compensated chronic HCV infection and their role in the peri-transplant setting remains to be defined. Clearly, this is challenging as the peri-transplant population is more vulnerable. Rapid emergence of drug resistance will prevent monotherapy with certain classes of DAAs including HCV protease inhibitors.[51] However, nucleoside or nucleotide analogous inhibiting the HCV polymerase as well as cyclophilin inhibitors show a very high resistance barrier and thus will likely be part of interferon-free regimens aiming to prevent HCV replication in the transplanted graft.[16,52] Potential drug–drug interactions have to be considered as several DAAs in clinical development for HCV infection are metabolized via the cytochrome P450 3A4 and thus may interfere with immunosuppressive agents.

Thus, several approaches to prevent graft re-infection are currently being pursued. At this stage, no clear favourite has emerged and the goal to prevent HCV reinfection may well remain elusive for several years to come.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....